title: Synthesis and antiprotozoal activity of dicationic m-terphenyl and 1,3-dipyridylbenzene derivatives.
abstract: 4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤ 10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina , Chapel Hill, North Carolina 27599-7525, United States.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Patrick
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ismail
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.forename: Trupti
authors.initials: T
authors.lastname: Pandharkar
authors.forename: Susan Kilgore
authors.initials: SK
authors.lastname: Jones
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001554:Benzene / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014355:Chagas Disease / Q000469:parasitology / Q000517:prevention & control; D005260:Female; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008956:Models, Chemical; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D011725:Pyridines; D013730:Terphenyl Compounds; D001554:Benzene